Multimodal MRI and blood-based epigenomic and protein-based multiomics profiling in mild neurocognitive disorder: a single-center cross-sectional observational study protocol

Introduction Mild neurocognitive disorder (mild NCD) is a clinically relevant stage of cognitive decline with heterogeneous clinical trajectories that remain poorly characterized, limiting efforts to identify early markers of disease progression. It may be associated with structural, functional, metabolic, CSF-related, and molecular features of the brain. This single-center, single-group, cross-sectional observational study aims to characterize multimodal imaging, cognitive, emotional, and blood-based molecular profiles in adults with mild NCD and to explore imaging–molecular associations for future hypothesis generation. Methods and analysis Sixty participants aged 50–85 years who meet DSM-5 criteria for mild NCD and satisfy MoCA-K and Short-form Geriatric Depression Scale screening criteria will be enrolled at Daejeon Korean Medicine Hospital of Daejeon University. Neuropsychological assessments will include the K-MMSE, SNSB-II, and ADAS-K-cog, and emotional response measures will be obtained using the emotional stimulus response test, which includes an emotion-inducing video, facial response recording, and self-report ratings. Blood-based multiomics assessments will include targeted plasma protein and cytokine profiling, APOE genotyping, and genome-wide DNA methylation profiling. Multimodal brain MRI will be performed at the Korea Basic Science Institute and will include structural MRI, resting-state and task-based functional MRI, magnetic resonance spectroscopy, and intravoxel incoherent motion imaging to deliver CSF-related indices. The main descriptive variables will consist of MRI-derived structural, functional, metabolic, and CSF-related indices. Secondary exploratory analyses will examine associations between MRI-derived indices, cognitive performance, emotional response measures, and blood-based molecular markers. Discussion Although this single-group, cross-sectional study cannot establish causality or directly validate diagnostic or predictive markers, it will characterize multimodal profiles in mild NCD and explore common imaging, cognitive, emotional, and blood-based molecular patterns. These findings will be interpreted as hypothesis-generating and may help prioritize candidate biomarkers for future longitudinal and comparative studies. Clinical trial registration https://cris.nih.go.kr , identifier KCT0011858.